The objectives of this project are 1) to evaluate the neuroendocrine responses to surgical stress and inflammation, 2) to determine the analgesic and anti-inflammatory effects of prototype and novel drugs which alter either the synthesis or the receptor activation of neuroendocrine mediators, and 3) to evaluate the clinical utility of these novel drugs in controlled clinical trials. Previous work on the physiologic function of plasma beta-endorphin and regulation of its release has provided evidence of enhanced release by a variety of stressors, including clinical pain following oral surgery and chest pain in patients with coronary artery disease. A current clinical study is attempting to measure inflammatory mediators released following surgery in order to determine the relationship between local levels of inflammatory mediators, clinical reports of pain, and their modulation by local infusion of prototypic drugs into the site of inflammation. Subjects undergoing the removal of an impacted third molar have a microdialysis fiber placed under the mucoperiosteal flap which is then slowly perfused to allow diffusion of mediators from the extracellular fluid into the perfusion fluid. Prostaglandin E2 is used as a marker of inflammatory mediators and increases postoperatively in the microdialylsate coincident with the onset of acute postoperative pain. Systemic administration of ketorolac decreases both pain and PGE2 levels, suggesting a functional relationship between NSAID analgesia and levels of locally released PGE2. A recent study demonstrated that administration of a very low dose of ketorolac (1 mg) administered directly into the extraction site at pain onset resulted in analgesia comparable to systemic administration of a normal therapeutic dose of 30 mg. Preliminary results suggest that peripheral administration of the NSAID is temporally related to decreased PGE2 levels at the extraction site. These data support a peripheral site of action of NSAIDs and provide a rationale for evaluating the effects of other peripherally administered drugs on pain and inflammatory mediators. Increasing evidence suggests that the nociceptive afferent barrage which can occur during a surgical procedure can activate central processes leading to an increased perception of clinical pain long after the nociceptive input is removed. This hypothesis was evaluated in the oral surgery model by randomly allocating local anesthesia or placebo anesthesia prior to the surgical removal of third molars with general anesthesia. Plasma levels of beta-endorphin, an index of activation of central pain pathways, was markedly elevated in the placebo group during surgery and at one hour postoperatively in comparison to the local anesthetic group. Pretreatment with a long-acting local anesthetic significantly reduced pain at the 48 hour observation, long after the local anesthetic has dissipated. Subjects also consumed significantly less analgesics over the 24-48 hour time period for pain. These data provide evidence to support the hypothesis that nociceptive afferent barrage produces central plasticity leading to increased postoperative pain.